Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Johanna I. Kiiski, Liisa M. Pelttari, Sofia Khan, Edda S. Freysteinsdottir, Inga Reynisdottir, Steven N. Hart, Hermela Shimelis, Sara Vilske, Anne Kallioniemi, Johanna Schleutker, Arto Leminen, Ralf Bützow, Carl Blomqvist, Rosa B. Barkardottir, Fergus J. Couch, Kristiina Aittomäki, Heli Nevanlinna

Research output: Contribution to journalArticle

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Abstract

Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair geneswere genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM ), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.

Original languageEnglish (US)
Pages (from-to)15172-15177
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number42
DOIs
StatePublished - Oct 21 2014

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Keywords

  • Breast cancer
  • DNA repair
  • Exome sequencing
  • FANCM
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • General

Cite this

Kiiski, J. I., Pelttari, L. M., Khan, S., Freysteinsdottir, E. S., Reynisdottir, I., Hart, S. N., Shimelis, H., Vilske, S., Kallioniemi, A., Schleutker, J., Leminen, A., Bützow, R., Blomqvist, C., Barkardottir, R. B., Couch, F. J., Aittomäki, K., & Nevanlinna, H. (2014). Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 111(42), 15172-15177. https://doi.org/10.1073/pnas.1407909111